There is strong seroepidemiologic evidence associating human cytomegalovirus (CMV) with Kaposi's sarcoma (KS), a malignancy suggested to be of endothelial cell origin. There has been an alarming increase in the incidence of KS associated with the ongoing epidemic of the Acquired Immunodeficiency Syndrome (AIDS). Although human T-cell lymphotropic virus Type III (HTLV-III) is the etiologic agent of AIDS, there is no evidence it directly causes KS. In KS tissues from patients with AIDS, HTLV-III DNA has not been found by in situ hybridization, whereas CMV DNA, RNA and antigens have been detected. Our hypothesis is that Kaposi's sarcoma has a multifactorial etiology. Under certain circumstances, endothelial cells infected with CMV become transformed. A viral infection as an initiating event, perhaps, could account for the multifocal distribution of this tumor. Maintenance of the transformed phenotype may be facilitated by the presence of angiogenesis factors or transforming growth factors. In a predisposed host, these abnormal cell transformants may be able to escape immune surveillance and cause tumors. CMV is a ubiquitous virus of the herpesvirus family and can cause acute, persistent, or latent infections in humans. There is evidence that CMV has oncogenic properties as well. CMV DNA sequences have been identified which have the ability to transform rodent cells which are tumorigenic in nude mice. Although CMV nucleic acids and antigens have been detected in KS tissue, CMV infection of human endothelial cells has not been extensively studied. It is important to determine if CMV is merely infecting these cells or whether it plays a role in the etiology of this tumor. Our objectives are to study CMV infection of endothelial cells and to determine if CMV can induce transformation. To accomplish this, we will test several CMV strains, including strain K9V, which was isolated from KS tissue. Even if endothelial cells are not permissive to viral replication, CMV may still be able to induce malignant transformation. In addition to using whole virus, we will study the ability of various DNA fragments to transform endothelial cells. We will determine whether angiogenesis factors (AF) are secreted by CMV-infected endothelial cells and whether AF potentiate transformation. Because the c-sis oncogene is expressed in endothelial cells, any amplification or change in this oncogene following infection will be determined. We expect to find complex interactions of CMV with human endothelial cells which may help clarify the role of CMV in Kaposi's sarcoma.